In response to the request for applications DK-05-011, entitled Animal Models of Diabetic Complications Consortium (AMDCC), the Investigators from the current AMDCC Neuropathy Phenotyping Core are proposing to develop 2 new mouse models of diabetic neuropathy (DN) targeting the biochemical pathways of oxidative stress. Our general strategic approach is to accelerate glucose-mediated oxidative injury in neurons in genetic models of type 2 diabetes. While many gene products participate in this process, we will concentrate on targeting 2 enzymes involved in superoxide detoxification: mitochondrial superoxide dismutase 2 (SOD2) and catalase. Our initial approach will concentrate on developing 2 Cre-loxP models on a susceptible genetic background. In parallel, we propose 2 hypothesis-driven specific aims for discovering the basic pathophysiologic mechanisms underlying DN.
Aim 1 will test the hypothesis that decreased catalase activity in sensory neurons will make these neurons more susceptible to glucose-mediated injury.
Aim 2 will test the hypothesis that animal models with DN have morphological and biochemical markers of increased oxidative stress in the peripheral nervous system. Information gained from this application will lead to new insights into the pathogenesis of DN and allow for the development of more relevant murine models of this disabling complication. Relevance to Public Health: 20 million Americans are diabetic and the incidence is increasing by 5% each year. Although DN is a common and highly morbid condition, there are no treatments for DN outside of control of the diabetic condition itself. Our studies will identify cellular targets for treatment of DN and have the potential to benefit all patients with diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK076160-05
Application #
7915659
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M1))
Program Officer
Ketchum, Christian J
Project Start
2006-09-30
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$287,132
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Callaghan, Brian C; Kerber, Kevin A; Banerjee, Mousumi et al. (2016) The evaluation of distal symmetric polyneuropathy: utilisation and expenditures by community neurologists. J Neurol Neurosurg Psychiatry 87:113-4
Callaghan, Brian C; Burke, James F; Feldman, Eva L (2014) How neurologists can choose (even more) wisely: prioritizing waste reduction targets and identifying gaps in knowledge. JAMA 311:1607-8
Hinder, Lucy M; Figueroa-Romero, Claudia; Pacut, Crystal et al. (2014) Long-chain acyl coenzyme A synthetase 1 overexpression in primary cultured Schwann cells prevents long chain fatty acid-induced oxidative stress and mitochondrial dysfunction. Antioxid Redox Signal 21:588-600
Callaghan, Brian C; Kerber, Kevin A; Lisabeth, Lynda L et al. (2014) Role of neurologists and diagnostic tests on the management of distal symmetric polyneuropathy. JAMA Neurol 71:1143-9
Kim, Bhumsoo; Backus, Carey; Oh, Sangsu et al. (2013) Hyperglycemia-induced tau cleavage in vitro and in vivo: a possible link between diabetes and Alzheimer's disease. J Alzheimers Dis 34:727-39
Hinder, Lucy M; Vincent, Andrea M; Hayes, John M et al. (2013) Apolipoprotein E knockout as the basis for mouse models of dyslipidemia-induced neuropathy. Exp Neurol 239:102-10
Sims-Robinson, Catrina; Hur, Junguk; Hayes, John M et al. (2013) The role of oxidative stress in nervous system aging. PLoS One 8:e68011
Hinder, Lucy M; Vivekanandan-Giri, Anuradha; McLean, Lisa L et al. (2013) Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes. J Endocrinol 216:1-11
Sims-Robinson, C; Zhao, S; Hur, J et al. (2012) Central nervous system endoplasmic reticulum stress in a murine model of type 2 diabetes. Diabetologia 55:2276-84

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